Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3

Am J Hum Genet. 2009 Aug;85(2):194-203. doi: 10.1016/j.ajhg.2009.07.007. Epub 2009 Aug 6.


Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; p(combined) = 3.9 x 10(-20) and 1.6 x 10(-19), respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; p(combined) = 8.97 x 10(-17)) and HLA-F (rs3129055 and rs9258122; p(combined) = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 x 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Asian People / genetics
  • Asian People / statistics & numerical data
  • Carcinoma / genetics*
  • Carcinoma / immunology
  • Case-Control Studies
  • Chromosomes, Human, Pair 6*
  • Cohort Studies
  • Female
  • Gene Frequency
  • Genome-Wide Association Study*
  • HLA Antigens / genetics*
  • Haplotypes
  • Histocompatibility Antigens Class I / genetics
  • Humans
  • Immunohistochemistry
  • Linkage Disequilibrium
  • Male
  • Nasopharyngeal Neoplasms / genetics*
  • Nasopharyngeal Neoplasms / immunology
  • Polymorphism, Single Nucleotide
  • Receptors, GABA-B / genetics
  • Receptors, GABA-B / metabolism
  • Taiwan


  • HLA Antigens
  • HLA-F antigens
  • Histocompatibility Antigens Class I
  • Receptors, GABA-B